Catalytic synthesis of new pyrazolo [3,4-b] pyridine via a cooperative vinylogous anomeric-based oxidation

In this study, a novel nano-magnetic metal–organic frameworks based on Fe3O4 namely Fe3O4@MIL-101(Cr)-N(CH2PO3)2 was synthesized and fully characterized. The prepared sample was used as catalyst in the synthesis of pyrazolo [3,4-b] pyridines as convenient medicine by condensation reaction of aldehydes, 5-(1H-Indol-3-yl)- 2H-pyrazol-3-ylamine and 3-(cyanoacetyl)indole via a CVABO. The products were obtained with high yields at 100 °C and under solvent-free conditions.

In recent years, many quests have been proceeded to investigate the biological and pharmaceutical properties of the nucleus with indole moieties. We have reviewed the reported methodologies for the synthesis of bis-and trisindolylmethanes 46 . Shiri has comprehensively reviewed the application of indoles in the multicomponent processes 47 . In this regard, fused N-heterocycles such as pyridines containing of indole moieties may be suitable candidates for biological and pharmacological chemistry investigations 48,49 . Because, N-heterocycles have been used as a drug candidate for antimicrobial, cancer, malaria, anticonvulsant, antifungal, HIV, anti-tumor, antioxidant, antihypertension and urinary incontinence treatment 50,51 . Furthermore, pyridine structure kernels are present in pharmaceutical materials and natural products 52 . Among the N-heterocycle compounds, pyrazolo [3,4b] pyridine scaffold is the valuable scaffold of material drugs and KDR kinase inhibition 53,54 . Recent research in material chemistry confirmed that pyrazolo [3,4-b] pyridine compounds are key intermediates in industry, semiconductors and organic light-emitting diodes 55 .
Anomeric effect (AE) as a fundamental example of stereoelectronic interaction has a great educational and research importance. It was discovered in 1955 by J. T. Edward in his studies of carbohydrate chemistry. Historically, this phenomenon was introduced to explain unusual conformational preferences in carbohydrates where the presence of endocyclic oxygen in a glycoside leads to an "abnormal" axial conformational preference for certain substituents at the anomeric carbon 56,57 . In an extension of the classic anomeric effect, a vinyl heteroatom is able to donate electron density from its lone pair through an adjacent π orbital and into the accepting σ* orbital on the other end of the double bond (Fig. 1a).

Result and discussion
Nowadays, synthesized molecules bearing pyridine-based scaffolds with indole moieties are attracted the attention of pharmaceutical chemistry researchers due to their building block's ability in pharmaceuticals and modern drug design approaches. So, there still is a great demand for the introducing of more practical and facile procedures and catalytic systems for multicomponent reactions in the organic synthesis field. On the other hand, the joining of indole, pyridine, and pyrazole moieties within a single molecule is our main research proposal in this investigation. We think that combining of above-mentioned units in a single structure can open up a new and promising insight in the course of rational design, synthesis and applications of drug candidate compounds. According to our recent findings [71][72][73][74][75][76][77][78] , we believed that the stereoelectronic effect has a major role in the last step of the proposed mechanism. To the best of our knowledge and literature surveys, there is no report on the synthesis of described pyridines. Therefore, herein we wish to report the first catalytic and multicomponent method for the preparation of new pyridines with both pyrazole and indole aromatic moieties via CVABO.
In order to extend the field of magnetic metal-organic frameworks catalysts, our research group has presented and synthesized a novel MIL-101(Cr)-N(CH 2 PO 3 H 2 ) 2 connected to Fe 3 O 4 tags (Fig. 2). The structure of Fe 3 O 4 @ MIL-101(Cr)-N(CH 2 PO 3 ) 2 as a magnetic metal-organic frameworks catalyst was characterized by FT-IR, XRD,  (Fig. 5) 79 . Also, the Scherer equation   (Table 1). For further verification of the scaffold and elemental analysis in the prepared catalyst, the energy dispersive X-ray analysis (EDX) analysis was used (Fig. 6a). The constituents of the catalyst were verified with the existence of Fe, N, Cr, O, C and P atoms. Figure 6b shows that the elementals of Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 are distributed uniformly.
In another study, the particle size and morphology of Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 as catalyst were studied by scanning electron microscope (SEM) (Fig. 7). As shown in Fig. 7 the particles have spherical shape in the nanoscale size.
The N 2 adsorption/desorption isotherms were utilized to analyze the textural features of Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 (Fig. 8a). A hysteresis loop is observed, indicating the presence of mesopores in the structure of the sample. The calculated surface area (BET) and the total pore volume are 100.03 m 2 g −1 and 0.518 cm 3 g −1 , respectively. The plot of the pore size distribution of Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 obtained by the BJH method is presented in (Fig. 8a). This plot reveals that the catalyst possesses both micropores (size < 2 nm) and mesopores (2 < size < 50 nm), however, the radius of most of the pores is less than 10 nm. Figure 8b  The thermal and behavioral stability of nano-magnetic metal-organic frameworks Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 were studied by thermal gravimetric (TG) and derivative thermal gravimetric (DTG) techniques (Fig. 9). The first step is the weight loss, which took place between 25 and 100 °C, associated with the removal of solvents (organic and water). The main stage of weight loss, disrupts the structure of Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 , took place at 380 °C, and includes about 35% weight loss. Therefore, this catalyst can be used up to 300 °C.   [3,4-b] pyridine derivatives with indole and pyrazole tags. The mentioned compounds were prepared by reaction of 4-chloro benzaldehyde (0.141 g, 1.0 mmol), 5-(1H-Indol-3-yl)-2H-pyrazol-3-ylamine (0.198 g, 1 mmol) and 3-(cyanoacetyl) indole (0.184 g, 1 mmol) as a suitable model for the optimization the reaction conditions. The results are assembled in Table 2, the best option for the preparation of compound C2 was achieved in the presence of 20 mg Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 in solvent-free conditions ( Table 2, entry 2). The target reaction was also examined by using several solvents such as DMF, CH 3 CN, MeOH, H 2 O, EtOH, CH 2 Cl 2 , CHCl 3 , and EtOAc (5 mL) in the presence of 20 mg of catalyst. The reaction results did not improve ( Table 2, entries 9-17). These interesting results encouraged us to synthesis a wide range of pyrazolo [3,4-b] pyridine compounds in solvent-free conditions.
As above-mentioned, after optimizing the reaction conditions, catalyst (20 mg) is used for the preparation of new biomolecules products using widespread aldehydes such as bearing electron-donating, electron-withdrawing groups, iso-trephetaldehyde and tris-aldehyde, 5-(1H-Indol-3-yl)-2H-pyrazol-3-ylamine and 3-(cyanoacetyl) indole. The results can be seen in Table 3, the obtained results show that the prepared catalyst is suitable for the synthesis of mono, bis and tris products with high yields (70-90%) and short reaction time (35-60 min).
In the suggested mechanism, the catalyst activates the carbonyl group of aldehyde.   (Fig. 11).
To compare the efficiency of the synthesized catalyst in the preparation of pyrazolo [3,4-b] pyridine derivatives, the model reaction (compound C2) was tested using various inorganic and organic catalysts under optimal conditions ( Table 4). As Table 4 shows, nano-magnetic metal-organic frameworks Fe 3 O 4 @MIL-101(Cr)-N(CH 2 PO 3 ) 2 is the best catalyst for the preparation of the desired product. Also, to investigate the heterogeneous nature of the protocols and palladium leaching, ICP/MS results proved that no Fe and Cr leaching was detected in the filtrate (Fe: 2.5 × 10 −6 and Cr: 1.9 × 10 −5 mol g −1 respectively) upon reaction completion, which indicates the high stability of the prepared catalyst.

Data availability
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request. www.nature.com/scientificreports/